A kind of extraction and purification process of Lovastatin
Technical field
The present invention relates to one kind isolated or purified Lovastatin or its pharmaceutically acceptable salt from microbial fermentation solution
Method.
Background technology
Lovastatin (Lovastatin) is called and is Ai Leting, its chemical entitled chemical name:(S) -2-Methyl Butyric Acid -
(1S, 3S, 7S, 8S, 8aR) -1,2,3,7,8,8a- hexahydro -3,7- dimethyl -8- { 2- [- 6 oxo -2- of (2R, 4R) -4- hydroxyls
Tetrahydrochysene, concrete structure formula are as follows:
Lovastatin is first generation statin substance, before being used as Statins active medicine Pravastatin now more
Body, therefore the yield of Lovastatin and quality directly affect cost and the purity of Pravastatin.
Existing extraction prepares the method for Lovastatin and mainly heats zymotic fluid, alkalizes and filter, and then filtrate is carried out
Extraction or resins exchange extraction is carried out to filtrate, using macroporous resin adsorption with reference to column chromatography technique exist cumbersome, carry
The low problem of high cost, long the production cycle, yield is taken, is gradually replaced by the method for solvent extraction.
But solvent extraction there is also defect.PCT Patent Application WO 9720834 elaborates that a kind of Lovastatin is carried
Method is taken, zymotic fluid is transferred to alkalescence with NaOH, then extracted with toluene and ethanol mixed solvent under agitation, in extract
Add substantial amounts of toluene and perlite, be acidified with nitric acid, the lower chlorination of stirring is imitated, press filtration, concentration, crystallize crude product is recrystallized again.
This method uses mixed solvent, reclaims difficulty, makes production operation become complicated using multiple solvents;Simultaneously 2 times in extraction process
PH is adjusted to more than 11, once to pH value 2 or so, is adjusted excessively frequently, and is proposed for the acidproof and alkaline-resisting of equipment
High request, easy etching apparatus.
A kind of new method is provided in PCT Patent Application WO 0063411:Zymotic fluid is readjusted the distribution to alkalescence with NaOH, at low temperature
Stirring, centrifugation are collected supernatant sulfuric acid and are adjusted to acidity, add butyl ester and the mixed solvent of normal octane to extract, centrifugation,
Extract low temperature crystallization concentrated in vacuo.Still extracted using mixed solvent in this invention, reclaim difficulty, alkaline extraction emulsification is tight
Weight, need to use substantial amounts of demulsifier, bring difficulty to subtractive process below;And the number of times for adjusting pH value is reduced to 2
Secondary, but remain strong acid and highly basic all occurs, still for the acidproof and alkaline-resisting of equipment proposes excessive demand, easily corrode
Equipment.
The Lovastatin extracting method that United States Patent (USP) US 2003215932 (A1) is illustrated is to be acidified simultaneously zymotic fluid sulfuric acid
Heating, stirring cyclisation at high temperature, then to zymotic fluid toluene extraction, filter residue soda solution and salt-free water washing, so
After carry out concentrated in vacuo, low temperature crystallization separate, washing.Initial in extraction process just just carries out cyclisation operation to zymotic fluid, needs
Fermentating liquid volume to be heated is huge, almost in the stage that overall extraction process volume is maximum, and also contains in zymotic fluid
Strong oxidizing property sulfuric acid, needs to consume the substantial amounts of energy and easy etching apparatus.
Content of the invention
It is an object of the invention to provide a kind of high income, energy-conservation, adapt to large-scale production from microbial fermentation solution
Separation and Extraction Lovastatin or the method for its pharmaceutically acceptable salt.
The invention before extraction bacteria residue, introduce the step of dry up bacteria residue, it is found that the step significantly can be carried
The yield of high Lovastatin crude product.Bacteria residue residual water after filtration, some hydrophilic impurity and readily volatilized impurity for being dissolved in water
The extraction in later stage and cyclisation efficiency can be directly affected Deng, these impurity, extend the time of cyclisation and extraction process.Bacteria residue was dried up
Cheng Zhong, is dissolved in some hydrophilic impurity and readily volatilized impurity of water etc. as vapor is removed, in addition, the bacteria residue after drying up
Weight is reduced, it is possible to reduce the consumption of organic solvent and the solution for washing used in follow-up extraction.
Specifically, the method bag of present invention isolated or purified Lovastatin or its pharmaceutically acceptable salt from zymotic fluid
Include following steps:
(1) Lovastatin zymotic fluid is taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 1.0-
5.0;
(2) filter, it is 10%-70% that bacteria residue is dried up to bacteria residue water content;
(3) in bacteria residue, add organic solvent, immersion to filter, the 1.0%- of filtrate volume 10% is added in filtrate
5.0% NaHCO3Solution, separates water layer, retains organic layer;
(4) organic layer is concentrated, concentrate cooling stirring, crystallization;The cyclization of Lovastatin enters in concentration
OK;
(5) filter, and the crude crystalline obtained with 10-20 DEG C of cold ethyl acetate washing and filtering, at 40 DEG C -50 DEG C or so
Dry crude crystalline and obtain Lovastatin crude product.
(6) by dissolving crude product in acetone, 50-60 DEG C is heated to, and uses activated carbon decolorizing, be filtered to remove activated carbon, dropped
Temperature is incubated 2-4 hours to 5-15 DEG C, and crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.
Preferably, in step (1), the concentrated sulfuric acid adjusts zymotic fluid pH to 3.0-4.0.
It is furthermore preferred that the concentrated sulfuric acid adjusts zymotic fluid pH to 3.5-4.0 in step (1).
Preferably, in step (2), bacteria residue is dried up and uses air at room temperature to dry up.
Preferably, in step (3) organic solvent be hydrophobic organic solvent, selected from but be not limited to butyl acetate,
In ethyl acetate, propyl acetate, Ethyl formate, hexanone, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, toluene, phenmethylol
One or several.
Preferably, in step (3), the addition of organic solvent and the input ratio of bacteria residue are, total throwing of organic solvent
Enter 1.0-10.0 times (V/W) of the amount equivalent to the total input amount of bacteria residue.
It is furthermore preferred that the addition of organic solvent and the input ratio of bacteria residue are in step (3), organic solvent total
4.0-6.0 times (V/W) of the input amount equivalent to the total input amount of bacteria residue.
Most preferably, in step (3), the addition of organic solvent and the input ratio of bacteria residue are, organic solvent total
4.5 times (V/Ws) of the input amount equivalent to the total input amount of bacteria residue.
Preferably, the temperature control that organic layer is concentrated in step (4) is at 40 DEG C -85 DEG C.
Preferably, in step (4), the condition of organic layer concentration is controlled to air pressure for -0.080MPa, and temperature is 55 DEG C,
Concentration time is 10 hours.
Preferably, in step (4) organic layer concentration condition be controlled to air pressure for atmospheric pressure when, temperature be 85 DEG C,
Concentration time is 40 hours.
Preferably, in step (4) during concentrate cooling stirring, mixing speed is 150rpm, and mixing time is 6-8
Hour.Control mixing speed extends mixing time so that crystal growth is slack-off, obtains bulky crude product in relatively low scope
Crystal, is easy to following filtration step.
The present invention from zymotic fluid from or purifying Lovastatin or the method for its pharmaceutically acceptable salt include following step
Suddenly:
(1) Lovastatin zymotic fluid is taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5-
4.0;
(2) filter, it is 40-50% that bacteria residue is dried up to bacteria residue water content;
(3) in bacteria residue, the ethyl acetate immersion 5-6 hours of bacteria residue weight 4.0-6.0 times are added to be filtered, to filtrate
The NaHCO of the 1% of middle addition filtrate volume 10%3Solution, filtrate separate water layer after standing;
(4) extraction filtrate is concentrated, during concentration, air pressure is more than -0.080MPa, and temperature is 55 DEG C, and concentration carries out 10
Individual hour, is concentrated into the small size of 5-7 times of product volume, then stirs the cooling of concentrate, crystallization;
(5) filter, and crude crystalline is washed with 10-20 DEG C of cold ethyl acetate, dry crude crystalline and obtain Lovastatin
Crude product.
(6) by dissolving crude product in acetone, 50-60 DEG C is heated to, and uses activated carbon decolorizing, be filtered to remove activated carbon, dropped
Temperature is incubated 2-4 hours to 5-15 DEG C, and crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.
When existing documents and materials disclose fermentation liquor pretreatment, can with acid adding or plus alkali, during acid adding pH value adjust to
1.0-5.0 or so, plus pH value is adjusted to 12.0 or so during alkali.According to actual production status of equipment, inventor selects to carry out acid adding
Process, and find that pH value is lower through repetition test, Lovastatin dissolving increases, but when pH is less than 3.5, Lovastatin
Dissolving increase become slow, and the lower corrosivity to equipment of pH value is bigger, increases equipment depreciation, increases production cost.
Therefore inventor selects to adjust pH value to 3.5-4.0 or so, the relation of Equilibrium yield and production cost.
According to the present invention from zymotic fluid from or purifying Lovastatin or its pharmaceutically acceptable salt method, carrying
Taking the initial stage has carried out pH value regulation to zymotic fluid, and extraction step afterwards is carried out under conditions of pH value is close to neutrality, whole
A pH value is only adjusted in set flow process, acid-base reagent has not only been saved, and has been alleviated the corrosion to equipment.In addition, extracting
Used in journey, single solvent ethyl acetate, is easy to the recovery of solvent;Ethyl acetate adds and only occurs in extraction and wash thick simultaneously
Product crystal, and after bacteria residue is dried up, add ethyl acetate again, the overall addition of ethyl acetate is few.
When zymotic fluid adjusts pH value to acidity or when extracting of the invention, does not carry out the cyclisation step that heats up
Suddenly, but remove intensification cyclisation the step of, shorten extraction needed for time.
Specific embodiment
The present invention is described referring to specific embodiment.It will be appreciated by those skilled in the art that these embodiments are only
For the present invention is described, which limits the scope of the present invention never in any form.
Embodiment 1
Experimental group 1 (with reference to CN 102344446)
Zymotic fluid 1L, is adjusted to pH1.5 with 5mol/L HCl, and stirring precipitation 1 hour is filtered, collects bacteria residue, in bacteria residue
0.25L butyl esters are added, stirring extraction bacteria residue 3 hours, separate, collect extract, be incubated at 30 DEG C under the conditions of 55 DEG C of temperature, plus
50ml 0.5mol/L NaOH agitator treatings 30 minutes, stand and go within 15 minutes eliminating water phase, organic are added to 50ml 0.5mol/L
HCl, agitator treating 30 minutes stand and go within 15 minutes eliminating water phase, organic be added to 50ml deionized waters, agitator treating 30 minutes,
Stand and go within 15 minutes eliminating water phase, organic phase carries out (temperature 65-70 DEG C, vacuum are less than 0.08MPa) concentrated in vacuo to volume about
30ml, cools to 12 DEG C, is incubated 3 hours, centrifugation dry crude product.
Experimental group 2 (with reference to US5712130)
The zymotic fluid of 1L Lovastatins, with salt acid for adjusting pH value to 3-5, reduces temperature to less than 20 degree, adds 500ml second
Acid butyl ester extracts 4 hours, and centrifugation retains organic phase, abandons water phase and bacteria residue.Organic phase at reduced pressure conditions 40 degree or so dense
Volume is reduced to for 50ml, is cyclized while concentration, concentrate is cooled below 20 degree, and standing a few hours are tied
Brilliant Lovastatin, Lovastatin is recrystallized.
Experimental group 3 (with reference to US2003215932A)
63.5ml 2N sulfuric acid is added in 1L zymotic fluids, and pH is warming up to 50-55 degree to 2.0, stirs 22 hours.
894.1mL toluene extractive fermentation liquid, organic extractant phase liquid 5% sodium acid carbonates of 157.6mL and 78.8mL distilled waters
Washing, washed organic extractant phase liquid are concentrated in vacuo to 23.5mL under 40-60 degree;Concentrate is cooled to 5-8 degree, stirring
2h, filters, and filter cake 15.3mL is cooled to the toluene of 5-10 degree in advance and washs, filtration cakes torrefaction, obtains Lovastatin.
Experimental group 4
1L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5-
4.0.
Filter, it is 50% that bacteria residue is dried up to bacteria residue water content.
In bacteria residue, the ethyl acetate immersion of 4.5 times of bacteria residue weight is added to be filtered for 5 hours, after the completion of filtration, to filter
The 1% of filtrate volume 10% NaHCO3 solution is added in liquid, water layer is separated after filtrate is stood 1.5 hours, retains organic phase.
Organic phase is concentrated, during concentration, air pressure is more than -0.080Mpa, and 55 DEG C or so carry out 10h, are concentrated into product
The temperature of concentrate is then down to 10 DEG C by 5 times of small sizes of amount, stirring insulation 6 hours, and mixing speed is 150rpm, crystallization.
Filtering, and crude crystalline being washed with 15 DEG C of cold ethyl acetate, drying thick wet product at 40 DEG C or so must cut down him to Lip river
Spit of fland crude product.
Experimental group 5
10L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5-
4.0,
Filter, it is 50% that bacteria residue is dried up to bacteria residue water content.
The ethyl acetate of 5.0 times of bacteria residue weight is added in bacteria residue, 85 DEG C are warming up to, and insulation cyclisation, after the completion of cyclisation, is entered
Row is filtered, and separates water layer after filtrate is stood, and retains organic phase.
Organic phase is concentrated, the temperature of concentrate is down to 10 DEG C then, stirring is incubated 6 hours, mixing speed is
150rpm, crystallization.
Filter, and wash crude crystalline with 15 DEG C of cold ethyl acetate, Lovastatin is obtained in the thick wet product of 40 DEG C of right drying
Crude product.
Experimental group 6
1L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5-
4.0,
Filter, it is 50% that bacteria residue is dried up to bacteria residue water content.
In bacteria residue, add the ethyl acetate immersion of 5.0 times of bacteria residue weight to be filtered for 5 hours, and use a small amount of ethyl acetate
Washing bacteria residue, after the completion of filtration, separates water layer, retains organic phase after filtrate is stood 1 hour.
Organic phase is concentrated, during concentration, air pressure is more than -0.080Mpa, and 55 DEG C or so carry out 10h, are concentrated into product
5 times of small sizes of amount, the temperature of concentrate is down to 10 DEG C then, stirring insulation 6 hours, mixing speed is 150rpm, knot
Brilliant.
Filtering, and crude crystalline being washed with 15 DEG C of cold ethyl acetate, drying thick wet product at 40 DEG C or so must cut down him to Lip river
Spit of fland crude product.
The Lovastatin crude product that experiment 1-6 is obtained is prepared Lovastatin finished product according to following steps:
By dissolving crude product in acetone, 55 DEG C are heated to, and use activated carbon decolorizing, be filtered to remove activated carbon, be cooled to 10
DEG C, 2 hours are incubated, crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.
The experimental result of experiment 1-6 is shown in Table 1.
Table 1, experiment 1-6 Lovastatin product yield lists
Conclusion:Cut down the Lip river that experimental group 4 be can be seen that from the experimental data of above table finished product Lovastatin yield and purity
Statin product yield has reached 82.0%, far above the Lovastatin product yield of experimental group 1-3,5-6.Experimental group 1-3,5-6
For comparative example, wherein experimental group 6 is on the basis of experimental group 4, removes and " adds filtrate volume 10% in filtrate
1% NaHCO3 solution " step, is the beneficial effect for illustrating to add the washing of NaHCO3 solution;And experimental group 5 is in experimental group 6
On the basis of the cyclisation step of enriching stage is moved to extraction while the experimental program that carries out, is that cyclisation step is described further
Position changes the impact to experimental program, and experimental group 4 is the method for the invention, and therefore, the method for the invention is better than right
Than the method for embodiment, mevastatin product yield is significantly improved.
Embodiment 2
1L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5-
4.0.
Filter, bacteria residue is dried up.
In bacteria residue, the ethyl acetate immersion of 5.0 times of bacteria residue weight is added to be filtered for 5 hours, after the completion of filtration, to filter
The 1% of filtrate volume 10% NaHCO3 solution is added in liquid, water layer is separated after filtrate is stood 1 hour, retains organic phase.
Organic phase is concentrated, during concentration, air pressure is more than -0.080Mpa, and 55 DEG C or so carry out 10h, are concentrated into product
The temperature of concentrate is then down to 10 DEG C by 5 times of small sizes of amount, stirring insulation 6 hours, and mixing speed is 150rpm, crystallization.
Filtering, and crude crystalline being washed with 15 DEG C of cold ethyl acetate, drying thick wet product at 40 DEG C or so must cut down him to Lip river
Spit of fland crude product.
By dissolving crude product in acetone, 55 DEG C are heated to, and use activated carbon decolorizing, be filtered to remove activated carbon, be cooled to 10
DEG C, 2 hours are incubated, crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.
Bacteria residue water content is dried up to 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 90% (without drying up
Bacteria residue), experimental result is shown in Table 2.
The impact that table 2, bacteria residue water content are extracted to Lovastatin
Conclusion:As can be seen from the table above, bacteria residue is dried up, and reducing bacteria residue water content can reduce adding ethyl acetate
Amount, extraction time, and yield and purity can be improved.Dry up bacteria residue to be conducive to improving extraction efficiency.
When bacteria residue water content falls further below 50%, ethyl acetate addition and extraction time still may proceed to
Bacteria residue water content reduces and reduces, and yield and purity increase slow with the reduction of bacteria residue water content or do not increase.Bacterium is described
During slag water content not higher than 50%, further reduce bacteria residue water content and can only reduce ethyl acetate addition and extraction time, receive
Rate and purity can't be obviously improved again;And water content is lower, the time lengthening for drying up is needed, the production time can be increased, therefore
Inventor determines that it is optimal working condition to dry up to bacteria residue water content bacteria residue for 40-50%.
Embodiment 3
1L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5.
Filter, bacteria residue is dried up to bacteria residue water content 40%.
In bacteria residue, the ethyl acetate immersion of 4.0 times of bacteria residue weight is added to be filtered for 5 hours, after the completion of filtration, to filter
The 1% of filtrate volume 10% NaHCO is added in liquid3Solution, separates water layer after filtrate is stood 1 hour, retain organic phase.
Organic phase is concentrated, concentration carries out 10h for 55 degree or so under reduced pressure, and the temperature of concentrate is down to 5 then
DEG C, stirring insulation 6 hours, mixing speed is 150rpm, crystallization.
Filtering, and crude crystalline being washed with 15 DEG C of cold ethyl acetate, drying thick wet product at 40 DEG C or so must cut down him to Lip river
Spit of fland crude product.
By dissolving crude product in acetone, 50 DEG C are heated to, and use activated carbon decolorizing, be filtered to remove activated carbon, be cooled to 5
DEG C, 4 hours are incubated, crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.
Embodiment 4
1L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5.
Filter, bacteria residue is dried up to bacteria residue water content 50%.
In bacteria residue, the ethyl acetate immersion of 6.0 times of bacteria residue weight is added to be filtered for 5 hours, after the completion of filtration, to filter
The 1% of filtrate volume 10% NaHCO is added in liquid3Solution, separates water layer after filtrate is stood 1 hour, retain organic phase.
Organic phase is concentrated, concentration carries out 10h for 40 degree or so under reduced pressure, and the temperature of concentrate is down to 5 then
DEG C, stirring insulation 6 hours, mixing speed is 150rpm, crystallization.
Filtering, and crude crystalline being washed with 10 DEG C of cold ethyl acetate, drying thick wet product at 50 DEG C or so must cut down him to Lip river
Spit of fland crude product.
By dissolving crude product in acetone, 60 DEG C are heated to, and use activated carbon decolorizing, be filtered to remove activated carbon, be cooled to 15
DEG C, 3 hours are incubated, crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.
Embodiment 5
1L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 4.0.
Filter, it is 50% that bacteria residue is dried up to bacteria residue water content.
In bacteria residue, the ethyl acetate immersion of 5.0 times of bacteria residue weight is added to be filtered for 5 hours, after the completion of filtration, to filter
The 1% of filtrate volume 10% NaHCO3 solution is added in liquid, water layer is separated after filtrate is stood 1.5 hours, retains organic phase.
Organic phase is concentrated, during concentration, air pressure is more than -0.080Mpa, and 55 DEG C or so carry out 10h, are concentrated into product
5 times of small sizes of amount, the temperature of concentrate is down to 10 DEG C then, stirring insulation 6 hours, mixing speed is 150rpm, knot
Brilliant.
Filtering, and crude crystalline being washed with 15 DEG C of cold ethyl acetate, drying thick wet product at 40 DEG C or so must cut down him to Lip river
Spit of fland crude product.
By dissolving crude product in acetone, 50 DEG C are heated to, and use activated carbon decolorizing, be filtered to remove activated carbon, be cooled to 8
DEG C, 2.5 hours are incubated, crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.
Embodiment 6
1L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5-
4.0.
Filter, it is 10% that bacteria residue is dried up to bacteria residue water content.
In bacteria residue, the butyl acetate immersion of 1.0 times of bacteria residue weight is added to be filtered for 5 hours, after the completion of filtration, to filter
The 5.0% of filtrate volume 10% NaHCO3 solution is added in liquid, water layer is separated after filtrate is stood 1.5 hours, is retained organic
Phase.
Organic phase is concentrated, during concentration, air pressure is more than -0.080Mpa, and 55 DEG C or so carry out 10h, are concentrated into product
7 times of small sizes of amount, the temperature of concentrate is down to 10 DEG C then, stirring insulation 6 hours, mixing speed is 150rpm, knot
Brilliant.
Filtering, and crude crystalline being washed with 20 DEG C of cold butyl acetate, drying thick wet product at 50 DEG C or so must cut down him to Lip river
Spit of fland crude product.
By dissolving crude product in acetone, 58 DEG C are heated to, and use activated carbon decolorizing, be filtered to remove activated carbon, be cooled to 12
DEG C, 3 hours are incubated, crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.
Embodiment 7
1L Lovastatin zymotic fluids are taken, and the concentrated sulfuric acid is slowly added under stirring the pH of zymotic fluid is adjusted to 3.5-
4.0.
Filter, it is 70% that bacteria residue is dried up to bacteria residue water content.
In bacteria residue, the toluene soak of 10.0 times of bacteria residue weight is added to be filtered for 5 hours, after the completion of filtration, in filtrate
The 1.0% of filtrate volume 10% NaHCO3 solution is added, water layer after filtrate is stood 1.5 hours, is separated, retains organic phase.
Organic phase is concentrated, during concentration, air pressure is more than -0.080Mpa, and 55 DEG C or so carry out 10h, are concentrated into product
7 times of small sizes of amount, the temperature of concentrate is down to 10 DEG C then, stirring insulation 6 hours, mixing speed is 150rpm, knot
Brilliant.
Filter, and wash crude crystalline with 20 DEG C of cold toluene, Lovastatin is obtained in the thick wet product of 50 DEG C or so drying thick
Product.
By dissolving crude product in acetone, 5460 DEG C are heated to, and use activated carbon decolorizing, be filtered to remove activated carbon, be cooled to
14 DEG C, 3.5 hours are incubated, crystallization, filtering for crystallizing liquid, 40-50 DEG C or so drying obtain Lovastatin finished product.